Submissions for variant NM_000304.4(PMP22):c.469C>T (p.Arg157Trp)

dbSNP: rs28936682

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000778488	SCV000914750	uncertain significance	PMP22-related disorder	2017-12-19	criteria provided, single submitter	clinical testing	The PMP22 c.469C>T (p.Arg157Trp) variant has been reported in two studies and is found in a total of four individuals, including three in a homozygous state and one in a heterozygous state (Parman et al. 1999; Brown et al. 2014). Parman et al. (1999) reported the p.Arg157Trp variant in a homozygous state in three siblings with a clinical diagnosis of Dejerine-Sottas disease, which is a historical name used to describe a severe and early childhood onset type of Charcot-Marie-Tooth disease (CMT). Their unaffected parents were reported to be first cousins and were both found to carry the p.Arg157Trp variant in a heterozygous state. Brown et al. (2014) identified the p.Arg157Trp variant in a heterozygous state in one individual who was referred for testing for hereditary neuropathy with liability to pressure palsies. The p.Arg157Trp variant was absent from 50 controls (Parman et al. 1999). It is reported at a frequency of 0.000015 in the European (non-Finnish) population of the Exome Aggregation Consortium, but this is based on one allele so the variant is presumed to be rare. Liu et al. (2014) studied the effect of the p.Arg157Trp variant and found an increase in formation of medium-sized aggregates, an increase in intracellular accumulation, a reduction of calnexin colocalization, and a low level of surface expression compared to wild type. Based on the evidence, the p.Arg157Trp variant is classified as a variant of unknown significance but suspicious for pathogenicity for PMP22-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Molecular Genetics Laboratory, London Health Sciences Centre	RCV001173916	SCV001337034	likely pathogenic	Charcot-Marie-Tooth disease		criteria provided, single submitter	clinical testing
Invitae	RCV001229968	SCV001402432	pathogenic	Charcot-Marie-Tooth disease, type I	2022-05-27	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 157 of the PMP22 protein (p.Arg157Trp). For these reasons, this variant has been classified as Pathogenic. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt PMP22 protein function. ClinVar contains an entry for this variant (Variation ID: 8444). This missense change has been observed in individuals with autosomal recessive Dejerine-Sottas disease (PMID: 10211478, 32719652). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs28936682, gnomAD 0.0009%).
Baylor Genetics	RCV001332355	SCV001524655	likely pathogenic	Hereditary liability to pressure palsies	2020-08-04	criteria provided, single submitter	clinical testing	This variant was determined to be likely pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
OMIM	RCV000008957	SCV000029169	pathogenic	Autosomal recessive Dejerine-Sottas syndrome	1999-04-01	no assertion criteria provided	literature only
GeneReviews	RCV000193053	SCV000243949	not provided	Charcot-Marie-Tooth disease type 1E		no assertion provided	literature only